The present invention relates to physical barriers for the prevention of adhesions, and more specifically, to a bioresorbable oxidized cellulose composite material composed of oxidized cellulose film for prevention of post-surgical adhesions.
Adhesions, or scar tissue bridges, are the abnormal connection of two or more body surfaces by fibrin associated with ingrowth of fibroblasts. Although the specific pathogenesis is not fully understood, such adhesions are likely produced as a result of the manipulative and chemical trauma associated with surgery. Such adhesions constitute a major source of postoperative morbidity and mortality. Indeed, up to ninety percent of all surgeries result in the formation of such adhesions and approximately ten percent of these adhesions result in serious complications for the patient. ELLIS, H., The Causes and Prevention of Intestinal Adhesions, BR. J. SURG. 69:241-43, 1982; WEIBEL M. A., MAJNO, G., Peritoneal Adhesions and their Relation to Abdominal Surgery, AM. J. SURG. 126:345-53, 1973. Such complications are location specific, but include infertility, intestinal obstruction, loss of range of motion in joints, and the like. For example, the formation of adhesions following cardiac surgery further increases the risks involved in a subsequent sternotomy. DOBELL A. R. C. AND JAIN, A. K., Catastrophic Hemorrhage During Redo Sternotomy, ANN. THORAC. SURG. 37: 273-78, 1984.
Potentially dangerous for patients and a nuisance for surgeons, adhesions have been the target of study for over a century. Previous attempts at prevention of adhesions can be classified as follows: (1) prevention of fibrin deposition; (2) removal of fibrin exudate; (3) inhibition of fibroblastic proliferation; and (4) separation of surfaces.
While each of these approaches have achieved a modicum of success, the use of physical barriers to limit tissue apposition during the healing period has yielded to date perhaps the most positive results. Wiseman, D. M., Polymers for the Prevention of Surgical Adhesions, in POLYMER SITE SPECIFIC PHARMACOTHERAPY, 369-421 (A. Domb ed. 1994)(John Wiley, Chichester, publisher). Early approaches to the use of physical barriers employed everything from fish bladder membranes to silver and gold foils. However, it was quickly realized that these attempts did not provide the prolonged effect necessary to prevent formation of adhesions. While more modern approaches have included the use of gels and liquids, the most promising approaches to date have utilized solid physical barriers.
One traditional approach to the use of a solid physical barrier includes the use of sheets of expanded polytetrafluoroethylene (xe2x80x9cPTFExe2x80x9d) to achieve the desired physical separation, as described in U.S. Pat. No. 5,468,505 to Hubbel et al. and by HANEY, A. F., HESLA, J., HURT, B., KETTLE, L. M., MURPHY, A. A., ROCK, J. A., ROWE G. and SCHLAFF, W. D., Prevention of Pelvic Sidewall Adhesion Reformation Using Surgical Barriers: Expanded Polytetrafluoroethylene (Gore-Tex(copyright) Surgical Membrane) is superior to Oxidized Regenerated Cellulose (Interceed(copyright) TC7), FERTIL. STERIL. (Prog. Supp.), p. 265, s. 210 (1994). While providing the desired physical separation of the tissues, the PTFE is nonabsorbable and therefore is not preferred. The high potential for infection caused by foreign materials left in the body is well known in the art.
Attempts to utilize physical barriers made from absorbable materials, such as polylactide, polyglycolide and their copolymers have achieved limited success partly because the porosity and fibrous nature of the material exacerbates the natural defense mechanism of the body to foreign materials. WISEMAN, D. M. Polymers for the Prevention of Surgical Adhesions in POLYMER SITE SPECIFIC PHARMACOTHERAPY, 369-421 (A. Domb ed. 1994)(John Wiley, Chichester, publisher). Barriers such as that marketed by Johnson and Johnson under the trade name INTERCEED(copyright) (TC7) Absorbable Adhesion Barrier have been more successful because they are composed of oxidized regenerated cellulose (xe2x80x9cORCxe2x80x9d) which is less reactive with tissue. However even barriers composed of ORC described in U.S. Pat. No. 4,840,626 to Linsky, et al. have achieved only limited usage due in part to the fact that: (1) the material contains pores which do not close rapidly enough on hydration to prevent the penetration of fibrin from one side of the barrier to the other. It is this fibrin bridging from one tissue to another that initiates adhesion formation. The inventors of the composite material of the present invention have discovered that for some applications, such as for the prevention of pericardial adhesions, or in circumstances where there is prolonged fibrin deposition due to inflammation, a more substantial barrier with smaller pores is required for adhesion prevention; and (2) the barrier may lose its integrity or position too rapidly at certain anatomical sites (e.g. around the heart) where there is organ movement to facilitate disintegration and dislodgment.
It is known that materials composed of oxidized cellulose evoke a minimal tissue response. This was first discovered in 1936 by W. Kenyon at the Eastman Kodak Laboratories. During Mr. Kenyon""s fundamental research on the oxidation of cellulose, it was discovered that a new type of product could be made by oxidizing cellulose using nitrogen dioxide. The new material was soluble in alkali and in contrast to the usual friable materials produced through other methods of oxidizing cellulose, the new material maintained its original form and much of its original tensile strength. It was shown that the new product was a copolymer of anhydroglucose and anhydroglucuronic acid. This new oxidized cellulose material was later developed into a bioabsorbable fabric hemostat by Parke Davis and Johnson and Johnson. A good discussion of the process can be found in the following references, all of which are incorporated herein by reference: Kenyon, R., Oxidation of Cellulose, INDUS.and ENGIN. CHEM., vol. 41 (1) 2-8, 1949; U.S Pat. Nos. 2,232,990, 2,298,387, 3,364,200 and 5,180,398 and its foreign equivalents, EP 0,492,990 and Japanese Application No. 361083/91.
Thus a need remains for a bioresorbable physical barrier for the prevention of postsurgical adhesions which is: (1) less porous than conventional woven or knitted fabric materials; (2) capable of being easily and securely attached to the desired location; and (3) does not contain pores which will permit deposition of fibrin and cellular ingrowth.
In accordance with one aspect of the present invention, a continuous composite film of oxidized cellulose is used as a physical barrier to limit tissue apposition, minimizing or preventing altogether the formation of postsurgical adhesions. The use of a continuous composite film overcomes the difficulties. The oxidized cellulose composite is constructed by forming a multi-layer sandwich of a cellulose film and an internal rip stop material, such as rayon, cellulose knitted, woven or non-woven fabric or cellulose paper. The films and fabric or paper are bonded together with a cellulosic adhesive such as starch, methylcellulose or oxidized with nitrogen dioxide which renders it bioabsorbable. Subsequently, it can be sterilized with gamma irradiation. This oxidation step converts the primary hydroxyl groups in the cellulose polymer to carboxyl groups and renders the polymer susceptible to aqueous and enzymic hydrolysis.) The resulting material is then usefull for the preparation of surgically implanted, bioabsorbable medical products. The resulting oxidized cellulose multi-layered composite film has all of the desirable characteristics (e.g. bioresorbability, suturability, low tissue reactivity etc.) of a bioabsorbable fabric composed of oxidized cellulose along with the additional benefits of a smooth, lubricious, continuous non porous surface in contact with tissue. Because the composite film contains a rip-stop material, it may be sutured in place for example as a pericardial patch.
Additionally the adherence of cells and molecules will be reduced on the smooth film surface compared with that of a fabric surface due to the lower surface area available for absorption. This feature greatly improves the success rate of the physical barrier. Adhesion of cells to substrates strongly influences many of their functions and therefore plays an important role in a variety of biologic processes including growth, phagocytosis, hemostasis and the response of tissue to implanted materials. In a symposium on Surface Characterization of Biomaterials, sponsored by the American Chemical Society September 1986, Buddy Ratner and others showed that smooth surfaces of biomaterial implants evoke less cellular reaction and less tissue irritation than rough surfaces.
Moreover, the oxidized cellulose multi-layered film is flexible, durable and, most importantly, suturable. The flexibility of the material is improved by moistening with saline or other physiologically acceptable fluid just prior to use. Accordingly, the multi-layered film can be easily and securely attached (e.g. via suturing) to the desired location. The oxidized cellulose multi-layered film also lacks tackiness and therefore will not stick to gloves or surgical instruments.
In another aspect of the present invention, the oxidized cellulose film can be used without its combination with a rip-stop material. Since the oxidized cellulose film alone will tear if sutured, the oxidized cellulose film can be secured into position with a physiologically acceptable tissue adhesive such as fibrin glue or a cyanoacrylate based adhesive. The oxidized cellulose film alone will function as a suitable physical barrier, the smooth nature of the film reducing the adherence of cells and molecules to its surface.
In yet another aspect of the present invention, the oxidized cellulose composite film material can be combined with drug treatments, such as heparin, to increase the efficacy of the barrier. Such drugs may be bonded to the composite either by surface absorption or by soaking the composite in a solution of the drug after oxidation and before complete drying. In a related application, the oxidized cellulose composite film material can be used as a wound dressing. Due to its flexibility and drug absorption qualities, the oxidized cellulose composite material serves as a unique wound dressing. Additionally, such wound dressing can be used to deliver one or more drugs to a wound site to aid in the healing of such wound.
In its process aspects, the present invention includes a method for forming the oxidized cellulose composite film material of the present invention. Additionally, another process aspect of the present invention is the prevention of postsurgical adhesions through the positioning as a physical barrier, between the site of the surgery and the neighboring tissue, of the oxidized cellulose composite film material of the present invention to limit tissue apposition.
The use of the oxidized cellulose composite film multi-layered physical barrier of the present invention provides the physical barrier necessary to limit tissue apposition, the bioresorbability of an ORC material, as well as ease and security of attachment and reduced biosensitivity to the material.
In yet another aspect of the invention, the oxidized cellulose film is used as a wound dressing. And in yet a different aspect of the invention, the oxidized cellulose film used as a wound dressing also serves as a drug delivery device, delivering one or more drugs to the wound site to aid in healing the wound.